RE-VERSE AD Trial: Idarucizumab for the Reversal of Anticoagulation by Dabigatran [Classics Series]

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

1. This study determined that idarucizumab is effective in reversing anticoagulation by the direct thrombin inhibitor Dabigatran.

2. Idarucizumab had an onset of action within minutes, supporting its use in emergency situations.

Original Date of Publication: June 2015

Study Rundown: The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial demonstrated that Idarucizumab could be used to rapidly reverse anticoagulation from dabigatran in patients with acute bleeding events or who required emergent surgery or other invasive intervention. Because of its inclusion of acutely ill patients, this study is more applicable to real clinical scenarios wherein rapid reversal of anticoagulation is required. However, this study is significantly limited by its small sample size, lack of a control group, and its use of laboratory tests as primary outcomes as opposed to more clinically relevant patient outcomes. This study was among the first to demonstrate the efficacy of idarucizumab, and subsequent larger-scale studies have since confirmed its efficacy. Idarucizumab is currently FDA-approved for the urgent reversal of the anticoagulant effects of dabigatran.

Click to read the study in NEJM

In-Depth [randomized control trial]: The RE-VERSE AD study aimed to determine if idarucizumab, a monoclonal antibody that binds and neutralizes thrombin-bound dabigatran, was effective in reversing dabigatran’s anticoagulant effects. This interim analysis included patients from 35 countries taking dabigatran who either required rapid reversal of anticoagulation for life-threatening bleeding, or who required it for urgent surgery or invasive procedures (n = 90). All patients were administered 5g of intravenous idarucizumab total, given as two 2.5mg bolus infusions, and blood samples were collected at various time points from baseline to 24 hours after the second bolus. The primary end point of this study was the maximum percent reversal of anticoagulation by dabigatran, as measured by dilute thrombin time and ecarin clotting time. Patients with normal values prior to their first idarucizumab dose were excluded from subsequent analysis. Secondary outcomes included the proportion of patients with complete normalization of these values, reduction in unbound dabigatran serum concentration, and clinical outcomes. Overall, the median maximum percentage reversal of anticoagulation was 100% in both groups, and reversal was evident within minutes (95%CI 100-100). The vast majority of patients had normal dilute thrombin time and ecarin clotting times after administration (between 88-98%), and at 4-hours after treatment, nearly all had unbound dabigatran concentrations near the lower limit of quantification (96%). A total of 21 patients had serious adverse clinical events, including 18 deaths.

Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. New England Journal of Medicine. 2015 Aug 6;373(6):511–20

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